Action Mechanism and Molecular Design of Indolepyrrodione Inhibitors Targeting IDO1

Xinmin Wang¹Zhigang Zhang²Kaixuan Hu²Wentong Yu²Yan Cheng¹Yuting Song¹Xin Sun²Siyao Li²Tiantian Yang²Jianping Hu²Jing Jing¹Ting Luo^1*

• ¹West China Hospital, Sichuan University, Chengdu, China
• ²Chengdu University, Chengdu, China

The incidence of cancer remains high, representing not only a major health threat to mankind but also a significant economic burden to society. While conventional therapies include surgery, radiotherapy, and chemotherapy, immunotherapy—particularly immune checkpoint inhibitors (ICIs)— has emerged as a promising approach to enhance anti-tumor immunity. Indoleamine 2,3-dioxygenase 1 (IDO1), a cytoplasmic enzyme regulating tryptophan catabolism, has become a key target for immunotherapeutic drug development. In this study, a series of molecular simulation methods were employed to investigate the molecular recognition and action mechanisms between representative indolepyrrodione (IPD) inhibitors (i.e. PF-06840003) and IDO1 in the field of pharmaceutical academic research. The results suggest that the substrate/inhibitor access channel valve (JK-loop) in the IDO1_apo system adopts an open conformation, which undergoes a transition to a closed state upon binding of the inhibitor PF-06840003. A potential inhibitory mechanism for PF-06840003 is proposed, in which the inhibitor forms extensive hydrogen bonds at the active site of IDO1, thereby restricting the movement of the JK-loop. This leads to both closure of the substrate L-Trp channel and reduction in the size of the O2/H2O small molecule channel, resulting in reduced efficiency of molecular entry and exit. Consequently, the catalytic function of the enzyme is attenuated. Based on these insights, a 3D-QSAR study was performed on 26 IPD analogs, establishing robust CoMFA and CoMSIA models with high stability and excellent predictive power. It should be noted that the potential highly inhibitory lead molecules designed in this study have their activities based on computer simulation predictions. They have not yet been verified through in vitro and in vivo experiments. Further experiments are needed to confirm their actual inhibitory effects and pharmacokinetic properties.